U.S. patent number 5,246,417 [Application Number 07/806,055] was granted by the patent office on 1993-09-21 for indicator for iontophoresis system.
This patent grant is currently assigned to ALZA Corporation. Invention is credited to Ronald P. Haak, David K. Roe, Felix Theeuwes.
United States Patent |
5,246,417 |
Haak , et al. |
September 21, 1993 |
Indicator for iontophoresis system
Abstract
Apparatus (11) for delivery of a medicament, drug or other
therapeutic agent transdermally to a body by iontophoresis is
provided. The apparatus (11) provides a means (13) for measuring
and displaying the cumulative amount of the medicament delivered to
the body by monitoring the amount of a metal, initially present at
the anode (45), that is transferred to the cathode (41) in a
subsidiary electrolyte cell (47) through which the drive current
for the apparatus (11) passes. Optionally, the apparatus also
provides a plurality of light emitting devices (63-1) that display
a measure of the cumulative amount of medicament delivered, by use
of visually distinguishable light colors or by use of binary
encoding in the light display.
Inventors: |
Haak; Ronald P. (San Jose,
CA), Theeuwes; Felix (Los Altos, CA), Roe; David K.
(Portland, OR) |
Assignee: |
ALZA Corporation (Palo Alto,
CA)
|
Family
ID: |
25193205 |
Appl.
No.: |
07/806,055 |
Filed: |
December 11, 1991 |
Current U.S.
Class: |
604/20;
607/152 |
Current CPC
Class: |
A61N
1/0448 (20130101); A61N 1/325 (20130101); A61N
1/044 (20130101); A61N 1/0436 (20130101) |
Current International
Class: |
A61N
1/32 (20060101); A61N 001/30 () |
Field of
Search: |
;128/798,802,803
;604/20 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
WO91/08795 |
|
Jun 1991 |
|
WO |
|
410009 |
|
May 1934 |
|
GB |
|
Other References
Dorland's Pocket Medical Dictionary, 23rd Ed., p. 362..
|
Primary Examiner: Rosenbaum; C. Fred
Assistant Examiner: Rafa; Michael
Attorney, Agent or Firm: Miller; D. Byron Meece; R. Scott
Mandell; Edward L.
Claims
We claim:
1. Iontophoresis apparatus that provides an indication of the
cumulative amount of a therapeutic agent delivered through a body
surface of a patient, the apparatus comprising:
a first electrode assembly containing a therapeutic agent to be
delivered and adapted to be placed in agent transmitting relation
with a body surface of a patient;
a second electrode assembly, adapted to be placed in ion
transmitting relation with the body surface at a location spaced
apart from the first electrode assembly;
an electrical current source, electrically connected to one of the
first and second, electrode assemblies;
a means for measuring the cumulative amount of electrical charge
transferred in a given time period as a function of the product of
current and time, which cumulative charge transferred is a relative
measurement of cumulative amount of agent delivered; and
a display means for displaying a visually perceptible output of the
cumulative amount of agent delivered relative to a total potential
dosage, said display means being electrically connected in series
with the first and second electrode assemblies and with the current
source.
2. The apparatus of claim 1, wherein said display means has a first
terminal and a second terminal and displays the cumulative amount
of electrical charge transferred between the first and second
terminals.
3. The apparatus of claim 2, wherein said measuring means and
display means comprise an anode having a selected metal coating on
its surface and electrically connected to one of said first
terminal and said second terminal, a cathode electrically connected
to the other of said first terminal and said second terminal, and
an electrolyte solution that surrounds at least a portion of the
anode and the cathode and provides an electrically conducting path
between the anode and the cathode and provides a path for transport
to the cathode of ions of the selected metal of the anode coating,
wherein visually perceptible amounts of metal are deposited at the
cathode, which deposition occurs upon reduction of metal cations at
the cathode during agent delivery.
4. The apparatus of claim 3, wherein said selected metal for said
anode coating is selected from the group consisting of copper,
silver, nickel, mercury, chromium, iron, lead and tin.
5. The apparatus of claim 3, wherein said electrolyte solution
comprises an aqueous solution of a water-soluble salt.
6. The apparatus of claim 3, wherein said electrolyte solution is
selected from the group consisting of sulfuric acid, citric acid,
phosphoric acid, pyrophosphoric acid, fluobric acid, oxalic acid
cyanide and ammonium hydride.
7. The apparatus of claim 3, wherein said electrolyte solution
includes dissolved metal ions of a predetermined concentration, the
metal ions being selected from the group consisting of copper,
silver, nickel, mercury, iron, lead and tin.
8. The apparatus of claim 1, wherein said current source comprises
a battery.
9. The apparatus of claim 8, wherein said current source further
comprises current control means for limiting said current so that
said current lies between predetermined lower and upper limits.
10. The apparatus of claim 8, wherein said current source includes
current control means for controlling said current in a
determinable, time-varying manner.
11. The apparatus of claim 10, wherein said current control means
comprises:
a resistor, having a first terminal and a second terminal, with its
first terminal connected to said current source;
a junction field effect transistor, having a source, a gate and a
drain, having its source electrically connected to the second
terminal of the resistor, having its gate electrically connected to
the first terminal of the resistor, and having its drain
electrically connected to said first electrode assembly.
12. The apparatus of claim 11, wherein said resistor is a variable
resistor having a predetermined range of resistance values.
13. The apparatus of claim 11, wherein said current control means
further comprises a second resistor of predetermined resistance
value that is connected between said drain of said field effect
transistor and one of said first and second electrode
assemblies.
14. The apparatus of claim 10, wherein said current control means
comprises:
a resistor, having a first terminal and a second terminal, with its
first terminal connected to said current source;
a junction field effect transistor, having a source, a gate and a
drain, having its source electrically connected to the second
terminal of the resistor, having its gate electrically connected to
the first terminal of the resistor, and having its drain
electrically connected to one of said first and second electrode
assemblies.
15. The apparatus of claim 14, wherein said resistor is a variable
resistor having a predetermined range of resistance values.
16. The apparatus of claim 14, wherein said current control means
further comprises a second resistor of predetermined resistance
value that is connected between said drain of said field effect
transistor and one of said first and second electrode
assemblies.
17. The apparatus of claim 10, wherein said current control means
includes patient-activated signal means, connected to said current
source, for delivering increased current of a predetermined
magnitude for a time interval of predetermined delivery length when
the patient-activated signal means is activated by the patient.
18. The apparatus of claim 17, wherein said current control means
delivers increased current of approximately constant magnitude
during at least a portion of said time interval.
19. The apparatus of claim 17, wherein said patient-activated
signal means includes lock-out means for precluding delivery of
said current of increased magnitude for a time interval of a
predetermined lock-out length after said patient-activated signal
means has been activated and has delivered said current of
increased magnitude.
20. The apparatus of claim 1, wherein said cumulative amount of
electrical charge delivered by the apparatus is divided into a
plurality of N non-overlapping ranges, the apparatus further
comprising a plurality of N activatable visible light devices,
numbered 1, 2, . . . , N, with each of said visible light devices
corresponding to a different one of the non-overlapping ranges of
said cumulative amount of electrical charge delivered and being
controlled and activated by said display means, whereby if said
cumulative amount of electrical charge delivered lies in one of the
non-overlapping ranges, one visible light device is activated and
displays light.
21. The apparatus of claim 1, wherein said cumulative amount of
electrical charge, denoted .DELTA..mu., delivered by the apparatus
is divided into a plurality of approximately 2.sup.N
non-overlapping ranges with a maximum value of .mu..sub.0, where N
is a predetermined positive integer, the apparatus further
comprising a plurality of at least N activatable visible light
devices, numbered k=1,2, . . . , N, that are controlled by said
display means so that if .DELTA..mu. satisfies the inequalities
##EQU2## with each coefficient n.sub.k =0 or 1, visible light
device number k is activated if n.sub.k =1 and is inactivated if
n.sub.k =0.
22. The apparatus of claim 1, wherein said cumulative amount of
electrical charge, denoted .DELTA..mu., delivered by the apparatus
is divided into a plurality of approximately 2.sup.N
non-overlapping ranges with a maximum value of .mu..sub.0, where N
is a predetermined positive integer, the apparatus further
comprising a plurality of at least N activatable visible light
devices, numbered k=1, 2, . . . , N, that are controlled by said
display means so that if .DELTA..mu. satisfies the inequalities
##EQU3## with each coefficient n.sub.k =0 or 1, visible light
device number k is activated if n.sub.k =0 and is inactivated if
n.sub.k =1.
23. The apparatus of claim 1, wherein the apparatus has a plurality
of L operating conditions associated therewith and numbered j=1, 2,
. . . , L, where L is a positive integer satisfying the
inequalities 2.sup.M-1 <L.ltoreq.2.sup.M for a predetermined
positive integer M, the apparatus further comprising a plurality of
M activatable visible light devices, numbered m=1,2, . . . , M and
controlled by said display means, so that, if operating condition
number j is present and the number j is expressible as ##EQU4##
where n.sub.m =0 or n.sub.m =1, visible light device number m is
activated if n.sub.m =1 and is not activated if n.sub.m =0.
24. The apparatus of claim 1, wherein the apparatus has a plurality
of L operating conditions associated therewith and numbered j=1,2,
. . . , L, where L is a positive integer satisfying the
inequalities 2.sup.M-1 <L.ltoreq.2.sup.M for a predetermined
positive integer M, the apparatus further comprising a plurality of
M activatable visible light devices, numbered m=1,2, . . . , M and
controlled by said display means, so that, if operating condition
number j is present and the number j is expressible as ##EQU5##
where n.sub.m =0 or n.sub.m =1, visible light device number m is
activated if n.sub.m =0 and is not activated if n.sub.m =1.
25. The apparatus of claim 1, wherein said first electrode assembly
comprises an electrically conducting layer and an ionically
conducting layer that contains said therapeutic agent in an ionized
or ionizable form.
26. The apparatus of claim 1, wherein said first electrode assembly
further comprises an ionically conducting adhesive layer,
positioned between and electrically connected to said first
electrode assembly and said body surface of said patient.
27. The apparatus of claim 1, wherein said second electrode
assembly comprises an electrically conducting layer and an
ionically conducting layer that contains an electrolyte in ionized
or ionizable form.
28. The apparatus of claim 1, wherein said first electrode assembly
further comprises an ionically conducting adhesive layer,
positioned between and electrically connected to said second
electrode assembly and said body surface of said patient.
29. The apparatus of claim 1, wherein the cumulative amount of
therapeutic agent delivered through the body surface is
substantially directly proportional to the cumulative amount of
charge transferred through the apparatus.
30. The apparatus of claim 1, wherein said display means comprises
a plurality of visible light emitting devices and means for
activating each of the devices at different non-overlapping ranges
of cumulative electrical charge passed through the apparatus.
31. The apparatus of claim 30, wherein each of said plurality of
visible light emitting devices displays a light having a color
visually distinguishable from the other visible light emitting
devices.
Description
TECHNICAL FIELD
This invention relates to an improved method for displaying the
amount of drug delivered transdermally by iontophoresis.
BACKGROUND ART
Iontophoresis is defined by Dorland's Illustrated Medical
Dictionary as "the introduction, by means of electric current, of
ions of soluble salts into the tissues of the body for therapeutic
purposes." Iontophoretic devices have been known since the early
1900's. British patent specification No. 410,009, published in
1934, describes an iontophoretic device that overcame one of the
disadvantages of such early devices known to the art at that time,
namely the requirement of a special low tension (low voltage)
source of current which meant that the patient needed to be
immobilized near such source. In that British specification, the
device was made by forming a galvanic cell from two electrodes plus
the material containing the medicament or drug to be transdermally
delivered. The galvanic cell produced the current necessary for
iontophoretically delivering the medicament. This ambulatory device
thus permitted iontophoretic drug delivery with substantially less
interference with the patient's daily activities.
The iontophoresis process has been found to be useful in the
transdermal administration of medicaments or drugs including
lidocaine hydrochloride, hydrocortisone, fluoride, penicillin,
dexamethasone sodium phosphate and many other drugs. Perhaps the
most common use of iontophoresis is in diagnosing cystic fibrosis
by delivering pilocarpine salts iontophoretically. The pilocarpine
stimulates sweat production; the sweat is collected and analyzed
for its chloride content to detect the presence of the disease.
Presently known iontophoretic devices use at least two electrodes,
positioned in intimate contact with some portion of the skin of the
body. A first electrode, called the active or donor electrode,
delivers the ionic substance, medicament, drug precursor or drug
into the body by iontophoresis. The second electrode, called the
counter or return electrode, closes an electrical circuit including
the body, the first electrode and a source of electrical energy,
such as a battery. For example, if the ionic substance to be driven
into the body is positively charged, the anode will be the active
electrode and the cathode will serve as the counter electrode to
complete the circuit. If the ionic substance to be delivered is
negatively charged, the cathode will be the active electrode and
the anode will be the counter electrode.
Alternatively, both the anode and cathode may be used to deliver
drugs of opposite electrical charge into the body. In this
situation, both electrodes are considered to be active or donor
electrodes. For example, the anode can drive a positively charged
ionic substance into the body, and the cathode can drive a
negatively charged ionic substance into the body.
It is also known that iontophoretic delivery devices can be used to
deliver an uncharged drug or agent into the body. This is
accomplished by a process known as electroosmosis. Electroosmosis
is the transdermal flux of a liquid solvent (e.g., the liquid
solvent containing the uncharged drug or agent) that is induced by
the presence of an electrical field imposed across the skin by the
donor electrode. As used herein, the terms "iontophoresis" and
"iontophoretic" refer to (1) the delivery of of charged drugs or
agents by electromigration, (2) the delivery of uncharged drugs or
agents by electroosmosis, (3) the delivery of charged drugs or
agents by the combined processes of electromigration and
electroosmosis, and/or (4) the delivery of a mixture of charged and
uncharged drugs or agents by the combined processes of
electromigration and electroosmosis.
Existing iontophoresis devices generally require a reservoir or
source of the ionized or ionizable species, or a precursor of such
species, that is to be iontophoretically delivered or introduced
into the body. Examples of such reservoirs or sources of ionized or
ionizable species include a pouch as described in the previously
mentioned Jacobson patent, U.S. Pat. No. 4,250,878, issued to
Jacobsen, or a pre-formed gel body as disclosed in U.S. Pat. No.
4,383,529, issued to Webster. Such reservoirs are electrically
connected to the anode or the cathode of an iontophoresis device to
provide a fixed or renewable source of one or more desired
species.
Recently, transdermal delivery of peptides and proteins, including
genetically engineered proteins, by iontophoresis has received
increasing attention. Generally speaking, peptides and proteins
being considered for transdermal or transmucosal delivery have a
molecular weight ranging between about 500 to 40,000 Daltons. These
high molecular weight substances are too large to passively diffuse
through skin at therapeutically effective levels. Because many
peptides and proteins carry either a net positive or net negative
charge, but are unable to passively diffuse through skin, these
substances are considered likely candidates for iontophoretic
delivery.
Iontophoresis is now being considered for long term delivery, over
periods of longer than 24 hours, of a number of drugs, including
peptides and proteins (e.g., insulin). As the length of delivery
increases, there is a need to develop small unobtrusive
iontophoretic delivery devices which can be easily worn on the skin
under clothing. One example of a small iontophoretic delivery
device designed to be worn on the skin is disclosed in U.S. Pat.
No. 4,474,570, issued to Ariura et al. Devices of this type are
powered by small, low voltage batteries. In addition to the need
for developing smaller iontophoretic delivery devices, there is a
need to reduce the cost of these devices in order to make them more
competitive with conventional forms of therapy such as pills and
subcutaneous injections.
One method of reducing cost is to use even lower voltage power
sources. Unfortunately, as the power source voltage decreases, the
drug delivery rate also decreases. Thus, there is a need for a
method of improving the performance characteristics, such as the
amount of drug delivered per unit of power, of iontophoretic
delivery devices to enable the use of inexpensive low-voltage power
sources. Further, a particular need exists for monitoring the
amount of medicament delivered, especially when the amount
delivered can vary or does not follow a predetermined pattern, as
in a patient-controlled (on-demand) and feedback-controlled
delivery system.
One method of increasing the rate at which drug is delivered from a
transdermal iontophoretic drug delivery device is to apply the
device on a skin site having optimum drug transport
characteristics. For example, in International Patent Publication
No. WO 91/08795, R. P. Haak et al discuss optimum skin sites for
attaching an iontophoretic drug delivery device to a human patient.
In a human patient, the patient's back appears to be the optimum
site for electrically assisted drug delivery, although the back
does not have the highest density of sweat ducts or skin pores for
iontophoretic transport.
During long-term iontophoretic drug delivery, it is difficult to
accurately estimate beforehand the amount of drugs that will be
delivered by iontophoresis over a selected time interval such as 24
hours. For example, either by design or because of uncontrollable
factors, such as battery discharge characteristics, the current
used to drive the iontophoresis process may vary over this time
interval. Further, environmental conditions, such as humidity,
temperature, perspiration and wetness, due to bathing, adjacent to
the delivery site may also vary with time. Either of these
uncertainties may produce uncertainties in the amount of drug or
medicament absorbed by the body over a long time interval.
Some workers have attempted to handle these uncertainties by
providing feedback regulation or polarity reversal of the applied
voltage so that the current, and thus the rate of delivery of
drug/medicament by iontophoresis, is kept approximately uniform
over a selected time interval. Polarity is sometimes reversed to
avoid skin irritation and to depolarize the skin. Skin polarization
is an obstacle to efficient electrotransport drug delivery.
Polarity control is disclosed in U.S. Pat. No. 4,116,238, issued to
Pettijohn, in U.S. Pat. No. 4,141,359, issued to Jacobsen, et al.,
in U.S. Pat. No. 4,406,658, issued to Lattin, et al., and in U.S.
Pat. No. 4,456,012, issued to Lattin. The complex electronics
required here uses devices such as transformers and SCR rectifiers,
and it may not be convenient or even possible to provide this in a
compact, lightweight package that can be worn by the patient under
clothing.
Other workers have provided means for selectively varying the
current delivered by the applied voltage near the site. McNichols
et al., in U.S. Pat. No. 4,725,263, disclose use of a current
control module for iontophoresis that can be mechanically trimmed
in order to change the current level used for this process.
However, only a small number, such as three, preselected current
values may be chosen, and the choice of current level usually
cannot be reversed. The mechanical trimming also serves as a simple
visual indicator of which current level has been chosen.
Sibalis discloses provision of a third electrode in a parallel
current loop in the iontophoresis process, in U.S. Pat. No.
4,708,716. This parallel current loop provides a feedback signal
that assertedly indicates when a desired dosage level is achieved
in the blood serum. A reverse plating cell is used here, in which
the resistance to current flow from anode to cathode increases
abruptly as metal or another electrically conductive material is
transferred (with the accompanying electrical charge) from an
active electrode to a counter electrode. However, this indicator,
which relies on an abrupt increase in resistance to charge flow,
appears to provide only two indicator levels.
An electronic control system for limiting total iontophoretic dose
is disclosed by Tapper in U.S. Pat. No. 4,822,334. The system
includes a voltage controlled osciallator whose oscillation
frequency is proportional to the current delivered to a load, such
as a patient's body that is receiving the dose. The number of VCO
cycles in a given time interval is counted to determine the load
current presently applied to and the dose delivered during that
time interval.
U.S. Pat. No. 4,942,883, issued to Newman, discloses use of a
sensing means in a housing for an iontophoretic device to
alternatingly turn on and turn off the current that delivers the
drug or medicament. The frequency of alteration of current turn on
and turn off may be of the order of 50 kHz, and may be controlled
by an on-board microprocessor.
The devices discussed above are often bulky and do not provide a
continuous indicator of cumulative dose delivered by iontophoresis.
What is needed is a compact, lightweight iontophoretic apparatus
that provides a continuous indicator of cumulative dose delivered
and, perhaps, of the status of certain other system variables, and
that can easily be worn adjacent to the delivery site for the drug,
medicament or other therapeutic agent.
DESCRIPTION OF THE INVENTION
These needs are met by the invention, which in one embodiment
includes first and second electrode assemblies electrically
connected to a source of electrical current. At least one of the
first and second electrode assemblies contains a therapeutic agent
to be delivered to a patient. The electrode assembly that contains
the therapeutic agent is adapted to be placed in therapeutic agent
transmitting relation with a body surface of the patient. The other
electrode assembly is adapted to be placed in ion transmitting
relation with the body surface at a location spaced apart from the
electrode assembly containing the therapeutic agent. A display
module is electrically connected between the current source and one
of the electrode assemblies. The display module displays the
cumulative amount of charge transferred through the module. The
measurement and display of cumulative transferred charge or current
may be performed by transfer of metal ions, such as copper ions,
from an anode to a cathode within the display module as the metal
ions flow from cathode to anode through a liquid electrolyte.
In another embodiment, a signal representing the cumulative current
.DELTA.Q that has passed through the medicament layer drives a
plurality of visible light devices (light emitting diodes, liquid
crystals, etc.) to display quantitatively a measure of .DELTA.Q.
This visual display may be color coded, using a plurality of
devices that display different colored light to indicate the
present range that .DELTA.Q lies in. Alternatively, the plurality
of visible light devices may be binary coded to display the present
range .DELTA.Q as a binary number, or to display both the present
range of .DELTA.Q and the status of other selected system variables
affecting system performance or accuracy.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 6 illustrate alternative embodiments of the
invention.
FIG. 2 is a more detailed view of a display module that is part of
the embodiment shown in FIG. 1.
FIG. 3 illustates one embodiment of a circuit suitable for
providing the current used to drive the invention.
FIG. 4 is a graphical view of medicament that might be delivered,
as a function of time, in a patient-controlled indicator system
according to the invention.
FIG. 5 illustrates one implementation of quantitative encoding and
display according to the invention.
MODES FOR CARRYING OUT THE INVENTION
FIG. 1 illustrates a first embodiment 11 of the invention,
including a current controller 31 (optional), a current source 33,
a display module 35 and first and second electrode assemblies 13
and 23. For purposes of illustration, the first or donor electrode
assembly 13 includes an electrically conducting layer 15, an
ion-conducting adhesive layer 17 (optional) and a medicament layer
19 positioned between and in electrical contact with the
electrically conducting layer 15 and either the adhesive layer 17
or the patient's body 21. The medicament layer 19 contains one or
more medicaments, drugs or other therapeutic agents that is to be
delivered transdermally to the body 21 by iontophoresis. The second
or counter electrode assembly 23, includes an electrically
conducting layer 25, an ion-conducting adhesive layer 27 (optional)
and a layer 29 containing an electrolyte salt. Alternatively, the
layer 29 may contain another medicament, drug or other therapeutic
agent. Electrolyte layer 29 is positioned between and electrically
connected to the electrically conducting layer 25 and either the
adhesive layer 27 or the patient's body. The second electrode
assembly 23 is spaced apart from the first electrode assembly 13 by
a suitable distance d that may be 0.5 mm-10 cm, although this
distance is not critical. The electrode assemblies 13 and 23 are
positioned so that their respective ion-conducting adhesive layers
17 and 27, if present, are directly in contact with the patient's
body 21. If the adhesive layer 17 or 27 is deleted, the
corresponding medicament layer 19 or electrolyte layer 29,
respectively, directly contacts the body, e.g., the skin. In either
case, the layers 19 and 29 are each in ion transmitting relation
with the surface of the body 21.
Electrically conducting layers 15 and 25 may be formed of a metal,
such as a metal foil or metal deposited or painted on as a suitable
backing. Examples of suitable metals include zinc, silver,
silver/silver chloride, aluminum, platinum, stainless steel, gold
and titanium. Alternatively, the electrically conducting layers 15
and 25 may be formed of a hydrophobic polymer matrix containing a
conductive filler, such as metal powder, powdered graphite, carbon
fibers or other known electrically conductive filler material. The
hydrophobic polymer-based electrodes may be made by mixing the
conductive filler in the hydrophobic polymer matrix. For example,
zinc powder, silver powder, silver/silver chloride powder, powdered
carbon, carbon fibers or mixtures thereof can be mixed in a
hydrophobic polymer matrix, such as polyisobutylene rubber, with
the preferred amount of conductive filler being within the range of
30-90 volume percent and the remainder being the hydrophobic
polymer matrix.
The electrically conducting layers 15 and 25 are electrically
connected to the current source 33, to the display module 35 and to
the optional current controller using well known means, for
example, by printed flexible circuits, metal foils, wires or
electrically conductive adhesives, or by direct contact. The
battery current source 33 may be supplemented by a galvanic couple
formed by conducting layers 15 and 25 that are composed of
dissimilar electrochemical couples. Typical galvanic couple
materials for delivering a cationic agent include a zinc conducting
layer 15 and a silver/silver chloride conducting layer 25. A
Zn-Ag/AgCl galvanic couple provides an electrical potential of
about one volt.
Regardless of the source of electrical current used, the current
source 33 in combination with the electrode assemblies 13 and 23
and the patient's body completes the circuit and generates an
electrical field across the body surface or skin to which the
device 11 is applied. This electrical field runs from the current
source 33, through the display module 35, through the electrically
conducting layer 25, through the electrolyte layer 29, through the
adhesive layer 27, through the body of the patient, through the
adhesive layer 17, through the therapeutic agent-containing layer
19, through the electrically conducting layer 15 and back to the
current source 33. The electrical field generated by the current
source 33 causes the therapeutic agent within the layer 19 to be
delivered through the adhesive layer 17 (optional) and into the
body by the process of iontophoresis.
Each of the medicament layer 19 and the electrolyte layer 29
preferably comprises a polymer matrix loaded with either a
therapeutic agent or with an electrolyte salt. The polymer matrix
of layers 19 and 29 may be comprised of a hydrophilic polymer,
preferably a mixture of a hydrophilic polymer and a hydrophobic
polymer, and most preferably a mixture of about 10-60 dry weight
percent of a hydrophilic polymer and about 10-60 dry weight percent
of a hydrophobic polymer. The medicament layer 19 and the
electrolyte layer 29 include a matrix that typically contains
0.5-60 dry weight percent drug and 0.5-60 dry weight percent
electrolyte, respectively.
As used herein, a hydrophilic polymer is a polymer having an
equilibrium water content of at least 20 weight percent, preferably
at least 30 weight percent, and most preferably at least 40 weight
percent, after prolonged exposure to an atmosphere having a
relative humidity of over 90 percent. As used herein, a hydrophobic
polymer is a polymer having an equilibrium water content of less
than 20 weight percent, preferably less than 15 weight percent, and
most preferably less than 10 weight percent, after prolonged
exposure to an atmosphere having a relative humidity of over 90
percent.
Preferably the hydrophobic polymer is heat fusible and can be heat
fused to another polymer surface, such as a polymer-based electrode
or membrane. Alternatively, if the electrically conducting layers
15 and 25 in FIG. 1 are composed of a metal, such as a metal plate,
a metal foil or a metallized surface on a suitable backing
material, the hydrophobic polymer may require a resinous tackifying
agent.
Suitable hydrophobic polymers for use in the matrices of the
therapeutic agent layer 19 and the electrolyte layer 29 include,
without limitation, the the following polymers: polyethylene;
polypropylene; polyisoprenes; polyalkenes; rubbers; copolymers such
as Kraton.RTM., polyvinylacetate and ethylene vinyl acetate
copolymers; polyamides such as nylons; polyurethanes;
polyvinylchloride; acrylic or methacrylic resins such as polymers
of esters of acrylic or methacrylic acids with alcohols such as
n-butanol, n-pentanol, isopentanol, isopentanol, 2-methyl butanol,
1-methyl butanol, 1-methyl pentanol, 2-methyl pentanol, 3-methyl
pentanol, 2-ethyl butanol, isooctanol, n-decanol or n-dodecanol,
alone or copolymerized with ethylenically unsaturated monomers such
as acrylic acid, methacrylic acid, acrylamide, methacrylamide,
N-alkoxymethyl acrylamides, N-alkoxymethyl methacrylamides,
N-tert-butylacrylamide and itaconic acid; N-branched alkyl maleamic
acid, wherein the alkyl group has 10-24 carbon atoms; glycol
diacrylates; and blends thereof. Most of the above-listed
hydrophobic polymers are heat fusible. Of the heat fusible,
hydrophobic polymers, polyisobutylene rubbers and ethylene vinyl
acetate copolymers are preferred.
Where the electrically conducting layers 15 and 25 are metal foils
or metallized polymeric films, it may be necessary to add a
tackifying resin to the hydrophobic polymer component in order to
enhance its adhesiveness. Suitable hydrophobic polymers that can be
rendered more adhesive by the addition of tackifying resins
include, without limitation, the following: cellulose acetate
butyrate; ethylcellulose; polyurethanes; poly(styrene-butadiene)
and poly(styrene-isoprene-styrene) block copolymers; ethylene vinyl
acetate copolymers, such as those described in U.S. Pat. No.
4,144,317, issued to Higuchi et al; plasticized or unplasticized
polyvinylchloride; natural or synthetic rubbers; and C.sub.2
-C.sub.4 polyolefins, such as polyethylene, polyisoprene,
polyisobutylene and polybutadiene. Examples of suitable tackifying
resins include, without limitation, fully hydrogenated aromatic
hydrocarbon resins, hydrogenated esters and low molecular weight
grades of polyisobutylene. Particularly suitable are tackifiers
sold by Hercules, Inc. of Wilmington, Del. under the trademarks
Staybellite Ester.RTM. #5 and #10, Regal-Rez.RTM. adb
Piccotac.RTM..
Suitable hydrophilic polymers for use in the matrices for the
layers 19 and 29 in FIG. 1 include the following:
polyvinylpyrrolidones; polyvinyl alcohol; polyethylene oxides, such
as Polyox.RTM., manufactured by Union Carbide, and Carbopol
manufactured by B. F. Goodrich of Akron, Ohio; blends of
polyoxyethylene or polyethylene glycols with polyacrylic acid, such
as Polyox.RTM. blended with Carbopol.RTM.; polyacrylamide;
Klucel.RTM.; cross-linked dextran, such as Sephadex (from Pharmacia
Fine Chemicals, AB, Uppsala, Sweden) or Water Lock.RTM. (from Grain
Processing Corp., Muscatine, Iowa), which is a
starch-graft-poly(sodium acrylate-co-acrylamide) polymer; cellulose
derivatives, such as hydroxyethyl cellulose, hydroxypropymethyl
cellulose and low-substituted hydroxypropylcellulose; cross-linked
Nacarboxymethylcellulose, such as Ac-Di-Sol (from FMC Corp.,
Philadelphia, Pa.); hydrogels, such as polyhydroxyethyl
methacrylate (from National Patent Development Corp.), natural
gums; chitosan; pectin; starch; guar gum; locust bean gum and the
like; and blends thereof. Of these, the polyvinylpyrrolidones are
preferred.
Blending of the drug or electrolyte with the polymer matrix is done
mechanically, either in solution or by milling, or hot melt mixing,
for example.
The layers 19 and 29 may contain, in addition to the drug and
electrolyte, other conventional materials, such as dyes, pigments,
inert fillers and other excipients.
The electrically conducting layer 15 of the first electrode
assembly 13 serves as an electrical contact for, and is
electrically connected to, a first current-carrying terminal of a
current controller 31 (optional) or of current source 33. A second
current-carrying terminal of the current controller 31 is
electrically connected to a first terminal (cathode or anode) of a
battery or other current source 33. The current controller 31,
which may be externally controllable or may be internally
configured to work automatically, controls the rate of charge flow
between its first and second terminals. This permitted rate of
charge flow may range between two predetermined limits, such as 0.1
milliamps and 1 milliamp ("mA"), or may be more precisely
controlled by a simple feedback circuit, including a differential
amplifier with a voltage input signal to one input terminal that is
used to control a current output signal in a static or time-varying
manner.
The current source 33, possibly regulated by the optional current
controller 31, may be a simple battery that provides a
substantially constant voltage difference between the first
terminal and a second terminal, or the current source 33 may
provide a time-varying current that varies slowly and in a
pre-programmed manner with time. Alternatively, the current source
33 and current controller 31 may provide a current that varies
between predetermined lower and upper limits. The second terminal
of the current source 33 is electrically connected to a first
terminal of a display module 35 that measures and/or visually
displays the cumulative amount of electrical charge transferred
from its first terminal to a second terminal of the display module
35. A second terminal of the display module 35 is connected to the
electrically conducting layer 25 of the second electrode assembly
23. A dermal or sub-dermal electrical path 37 in the patient's body
21 completes an electrical circuit that includes the donor
electrode assembly 13, the current source 33, the display module 35
and the counter electrode assembly 23, shown in FIG. 1.
FIG. 2 illustrates an embodiment of the display module 35 of FIG. 1
in more detail. The display module 35 receives electrical charge on
a first current-carrying line 39 that is electrically connected to
a cathodic terminal 41 of the module 35. The display module 35
transfers electrical charge to a second current-carrying line 43
that is electrically connected to an anodic terminal 45. The anodic
terminal 45 preferably includes a metal coating of copper, silver,
nickel, mercury, chromium, iron, lead, tin or similar material, and
the cathodic terminal 41 may be a different, electrically
conducting material. Electrical charge is transferred from anodic
terminal to cathodic terminal through oxidization and reduction of
a chemical species. An ionic species is generated by the
oxidization reaction at the anodic terminal 45. This ionic species
is then conducted through an electrolyte solution 47 positioned
between the cathodic terminal 41 and the anodic terminal 45. The
conducted ionic species is consumed by the reduction reaction
occurring at the cathodic terminal 41. The solution 47 may
initially contain dissolved cations, such as Cu.sup.+, which are
subsequently electroplated onto the cathodic terminal 41 to provide
improved initial response of the iontophoretic transport of the
medicament. The electrolyte solution 47 may be any conventional
electroplating bath solution, including but not limited to sulfuric
acid, citric acid, phosphoric acid, pyrophosphoric acid, fluoboric
acid, oxalic acid cyanide or ammonium hydride. If a cation is to be
dissolved in the electrolyte solution, the electrolyte itself
should be chosen based upon the choice of cation. A tube or other
flow enhancement means 49 (optional) may be positioned between the
anodic terminal 45 and the cathodic terminal 41 to promote and
control flow to the cathodic terminal 41 of the metal cations
liberated at the anodic terminal 45.
As the liberated cations accumulate at the cathodic terminal 41 and
are reduced electrochemically, i.e., electroplated, the cumulative
mass of these ions thereat can be quantitatively displayed by
visual means. The cumulative mass of these ions is approximately
proportional to the time integral of the current i(t), viz.
between anodic terminal and cathodic terminal for the time interval
[t.sub.0,t] of interest. The incremental charge .DELTA.Q in Eq. (1)
is measured in Coulombs, and the Coulomb-measuring device 35 shown
schematically in FIG. 2 should consume less than 100 millivolts in
operation. The embodiment 11 shown in FIG. 1 can easily be
incorporated into a transdermal iontophoresis device. If visual
display means for the cumulative charge .DELTA.Q is to be provided,
the display module 35 should be provided with a transparent backing
material, such as clear plastic, for one surface.
Growth of the metal ions deposited on the cathodic terminal 41 is
approximately related to the time-integrated current .DELTA.Q by
the relationship
where
.DELTA.m=cumulative mass of ions deposited at cathodic
terminal,
Z=oxidization state of metal ion to be deposited on cathodic
terminal,
F=Faraday constant=96,487 Coulombs per equivalent,
M=atomic weight of anode metal coating (e.g., 63.5 for Cu).
For example, 10 hours of uniform current of 1 mA will produce a
cumulative mass deposit .DELTA.m of 11.8 micrograms of Cu at the
cathodic terminal. For some anode metals of interest, then,
.DELTA.m and .DELTA.Q are approximately linearly related by the
equations
where k is a material constant given by
The k values for the preferred metal coatings for the invention are
as follows.
The relationship between cumulative ion mass .DELTA.m and
time-integrated current .DELTA.Q need not be linear, as suggested
in Eq. (2), as long as cumulative ion mass .DELTA.m is a known,
strictly monotonically increasing function of .DELTA.Q. A variable
y=f(x) is said to be a monotonically increasing function of the
variable x if, for any two values x.sub.1 and x.sub.2 for which
f(x) is defined with x.sub.1 <x.sub.2, the inequality
f(x.sub.1).ltoreq.f(x.sub.2) holds; y=f(x) is strictly
monotonically increasing if x.sub.1 <x.sub.2 implies
f(x.sub.1).ltoreq.f(x.sub.2).
Several control features are central to operation of this
invention. First, action of the channel for metal deposited on the
cathodic terminal, defined by the tube 49 in FIG. 2, must be
reproducible. Second, the anodic terminal 45 and cathodic terminal
41 must be reproducibly fabricated. Third, the composition of the
liquid electrolyte 47 positioned between and surrounding the anodic
terminal 45 and cathodic terminal 41 should be chosen to produce a
smooth, uniform deposit of metal ions on the cathodic terminal.
FIG. 3 illustrates one suitable circuit that can be used for the
current controller 31 shown in FIG. 1. The current source 33 of
FIG. 1 may, for example, be three Li batteries connected in series
to provide a voltage difference of approximately 9 Volts, with the
low voltage electrode of the battery being connected across a
resistor 51 to the source of an junction field effect transistor
("JFET") 53. The current source 33 is connected directly to the
gate of the JFET 53. The resistor 51 may have a variable
resistance, with an impedance swing of 100 kilo-ohms, or may have a
fixed resistance value in the range of 10-100 kilo-ohms. The JFET
53 may be the 2N4220 or any equivalent transistor. The drain of the
JFET 53 is connected across a current-measuring and
current-limiting resistor 55 (optional), preferably with a
resistance value of about 100 Ohms, to the conducting layer 25 of
the second electrode assembly 23 shown in FIG. 1. The high voltage
terminal of the power supply 33 is connected directly to the
conducting layer 15 of the first electrode assembly 13 to complete
the circuit. If the resistance between gate and source of the JFET
53 is increased or decreased by a variable resistor 51, the charge
flowing from source to drain will decrease or increase,
respectively, in a predictable manner. Thus, a means is provided to
increase or decrease the current, and thus to control the rate at
which the medicament enters the body through iontophoretic
action.
In some instances it may be desirable to allow a patient to
self-administer a bolus dose of medication, such as an analgesic,
during periods of severe pain. Such a device would have control
features that allow the patient to deliver such medicament at a
rate greater than the long term rate for short periods of time.
This increased delivery rate may be implemented, upon demand by the
patient at a time t=t.sub.1, by increase of the current i(t)
delivered to the iontophoretic cell from the long term current
value i.sub.0 to a larger current value i.sub.1, corresponding to
delivery of a "bolus" dose to the patient, for a time interval
t.sub.1 .ltoreq.t.ltoreq.t.sub.2 of fixed length .DELTA.t=t.sub.2
-t.sub.1, as illustrated in FIG. 4. Subsequent demands for
increased delivery rate at later times t=t.sub.3 and t=t.sub.5 will
result in new increases of the current value from i.sub.0 to
i.sub.1, over the time intervals t.sub.3 .ltoreq.t.ltoreq.t.sub.4
and t.sub.5 .ltoreq.t.ltoreq.t.sub.6, where the time interval
lengths t.sub.4 -t.sub.3 =t.sub.6 -t.sub.5 =.DELTA.t=constant. In
practice, the time interval length .DELTA.t can cover a broad
range. In a more sophisticated version, if the patient has demanded
and received medicament at an increased rate corresponding to the
current i.sub.1 for a time interval t.sub.1
.ltoreq.t.ltoreq.t.sub.2, the patient might be "locked out" so that
the system would not respond to another such demand for a time
interval t.sub.2 .ltoreq.t.ltoreq.t.sub.3, where t.sub.3 -t.sub.2
is predetermined.
FIG. 5 illustrates an embodiment 61 of a visual indicator for
iontophoretic delivery of medicaments or drugs to a patient, in
which precisely one of a plurality of N light emitting diodes,
liquid crystals or other suitable visual indicators (collectively
referred to as "visible light devices" or "VLDs" herein for
convenient reference) 63-1, 63-2, 63-3, . . . 63-N is lit (or
otherwise activated), corresponding to the cumulative amount of
medicament delivered to the patient in a predetermined time
interval, such as 24 hours. A VLD, when lit, would indicate that an
amount (mass) of medicament .DELTA..mu. lying in a range
.DELTA..mu..sub.n <.DELTA..mu..ltoreq..DELTA..mu..sub.n+1 (n=1,
2, . . . , N) has been delivered, where .DELTA..mu..sub.1
<.DELTA..mu..sub.2 < . . . .DELTA..mu..sub.N. In one mode of
operation of this embodiment, each of the plurality of VLDs would,
when lit, display a color that is visually distinguishable from the
color of each of the other VLDs. For example, the colors of the
VLDs 63-1, 63-2, 63-3, . . . , 63-N might be blue, blue green,
green, . . . , and red, respectively, so that a person monitoring
the VLD display could immediately visually determine the range of
the cumulative medicament delivered. The order of arrangement of
colored, visually distinguishable VLDs is not importance in this
mode.
In a second mode of this embodiment, the N VLDs may be ordered or
numbered 1, 2, . . . , N and encoded binarily to provide a more
precise measure of the cumulative amount of medicament delivered.
For example, if the cumulative amount of medicament delivered
.DELTA..mu. satisfies the inequalities ##EQU1## where
.DELTA..mu..sub.0 is the maximum value of the quantity .DELTA..mu.
deliverable and each of the quantities n.sub.k is either 0 or 1,
VLD 63-k could be illuminated if n.sub.k =1 and could be
non-illuminated if n.sub.k =0. For example, if N=4 and VLDs 63-1
and 63-3 are the only VLDs illuminated, this would indicate that
the quantity .DELTA..mu. lies in the range 0.625 .mu..sub.0
<.DELTA..mu..ltoreq.0.75 .mu..sub.0, corresponding to the binary
pattern 1 0 1 0.
One advantage of this mode is that the cumulative amount of
medicament delivered is displayed with improved accuracy, with an
error of no more than .DELTA..mu..sub.0 /2.sup.N. The VLD pattern
is encoded digitally here, using a base of two (n.sub.k =0 or 1).
Any other suitable integer base P (P.gtoreq.2) could also be used.
Here, more than one VLD could be simultaneously illuminated and the
VLDs would not be color coded so that it might not be possible to
visually determine or estimate the cumulative amount of medicament
delivered at a glance. This could be advantageous, if information
on the cumulative amount of medicament delivered is not to be
shared with the patient.
A third mode of the embodiment 61 shown in FIG. 5 would merely
illuminate a single one of the VLDs, as in the first mode, but the
VLDs would not be color coded. The VLDs in this mode would be
ordered 1, 2, . . . , N, and the position of the particular VLD
that is lit would determine the range of the comulative amount of
medicament delivered.
In a fourth mode of the embodiment 61, using N=4 VLDs of no
particular color or colors, the four VLDs would be ordered and
digitally encoded as in the second mode, but the four-place binary
code (n.sub.1, n.sub.2, n.sub.3, n.sub.4) would be interpreted as
follows.
______________________________________ Group Status n.sub.1 n.sub.2
n.sub.3 n.sub.4 Interpretation
______________________________________ 0 0 0 0 System not
functioning 0 0 0 1 Resistance too high; current not at desired
level 0 0 1 0 Resistance too low; current terminated 0 0 1 1 System
operating satisfactorily 0 1 0 0 Cumulative delivery is 0-25% 0 1 0
1 Cumulative delivery is 25-50% 0 1 1 0 Cumulative delivery is
50-75% 0 1 1 1 Cumulative delivery is 75-100% 1 0 0 0 0-25% of
bolus dose utilized 1 0 0 1 25-50% of bolus dose utilized 1 0 1 0
50-75% of bolus dose utilized 1 0 1 1 75-100% of bolus dose
utilized 1 1 0 0 75-100% of battery remains 1 1 0 1 50-75% of
battery remains 1 1 1 0 25-50% of battery remains 1 1 1 1 Under 25%
of battery remains ______________________________________
This mode requires provision of a means to query the system and to
provide signals to illuminate the appropriate VLDs. This indicator
system divides naturally into four mutually exclusive groups of
four indicia or binary signals each: (1) group 1 (binary values
0,1,2,3; n.sub.1 =0, n.sub.2 =0) displays the resistance values and
functioning or malfunctioning of the system as a whole; (2) group 2
(binary values 4,5,6,7; n.sub.1 =0, n.sub.2 =1) displays the
commulative current delivered thus far; group 3 (binary values
8,9,10,11; n.sub.1 =1; n.sub.2 =0) displays the amount of bolus
dose utilized thus far; and group 4 (binary values 12,13,14,15;
n.sub.1 =1, n.sub.2 =1) displays the battery capacity remaining for
the system. One button, corresponding to four different binary
values, would be used to choose or to cycle through the four
groups; and as each of the four groups is chosen, two VLDs would
display one of the four (=2.sup.2) status or condition indicia
present within that group, using the indices n.sub.3 and
n.sub.4.
The terms "drugs", "medicaments" and "therapeutic agents" are used
interchangeably and are intended to have their broadest
interpretation, namely any therapeutically active substance that is
delivered to a living organism to produce a desired, usually
beneficial, effect. This includes therapeutic agents in all the
major therapeutic areas including, but not limited to:
anti-infectives, such as antibiotics and antiviral agents;
analgesics, including fentanyl, sufentanil, buprenorphine and
analgesic combinations; anesthetics; anorexics; antiarthritics;
antiasthmatic agents, such as terbutaline; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
antihistamines; antiinflammatory agents; antimigraine preparations;
antimotion sickness preparations, such as scopolamine and
ondansetron; antinauseants; antineoplastics; antiparkinsonism
drugs; antipruritics; antipsychotics; antipyretics; antispasmodics,
including gastrointestinal and urinary; antocholinergics;
sympathomimetrics; xanthine derivatives; cardiovascular
preparations, including calcium channel blockers such as
nifedipine; beta blockers; beta-agonists, such as dobutamine and
ritodrine; antiarrythmics; antihypertensives, such as atenolol; ACE
inhibitors, such as rinitidine; diuretics; vasodilators, including
general, coronary, peripheral and cerebral; central nervous system
stimulants; cough and cold preparations; decongestants;
diagnostics; hormones, such as parathyroid hormone; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
parasympathomimetrics; prostaglandins; proteins; peptides;
psychostimulants; sedatives; and tranquilizers.
The invention is also useful in the controlled delivery of
peptides, polypeptides, proteins and other macromolecules. These
macromolecular substances typically have a molecular weight of at
least 300 Daltons, and more typically have a molecular weight of
300-40,000 Daltons. Specific examples of peptides and proteins in
this size range include, without limitation, the following: LHRH;
LHRH analogs, such as buserelin, gonadorelin; napharelin and
leuprolide; GHRH; GHRF; insulin; insulotropin; heparin; calcitonin;
octreotide; endorphin; TRH; NT-36 (chemical name is
N=[[(s)-4-oxo-2-azetidinyl] carbonyl]-L-histidyl-L-prolinamide);
liprecin; pituitary hormones, such as HGH, HMG, HCG and
desmopressin acetate; follicle luteoids; aANF; growth factors, such
as growth factor releasing factor (GFRF); bMSH; somatostatin;
bradykinin; somatotropin; platelet-derived growth factor;
asparaginase; bleomycin sulfate; chymopapain; cholecystokinin;
chorionic gonadotropin; corticotropin (ACTH); erythropoietin;
epoprostenol (platelet aggregation inhibitor); glucagon; hirulog;
hyaluronidase; inteferon; interleukin-1; interleukin-2; menotropins
(urofollitropin (FSH) and LH); oxytocin; streptokinase; tissue
plasminogen activator; vasopressin; desmopressin; ACTH analogs;
ANP; ANP clearance inhibitors; angiotensin II antagonists;
antidiuretic hormone agonists; antidiuretic hormone antagonists;
bradykinin antagonists; CD4; ceredase; CSFs; enkephalins; FAB
fragments; IgE peptide suppressors; IGF-1; neurotrophic factors;
colony stimulating factors; parathyroid hormone and agonists;
parathyroid hormone antagonists; prostaglandin antagonists;
pentigetide; protein C; protein S; renin inhibitors; thymosin
alpha-1; thrombolytics; TNF; vaccines; vasopressin antagonist
analogs; alpha-1 anti-trypsin (recombinant); and TGF-beta.
As an alternative to side-by-side alignment of the donor electrode
assembly 13 and the counter electrode assembly 23, shown in FIG. 1,
these electrode assemblies can be concentrically aligned, with the
counter electrode assembly 81 being centrally positioned and being
surrounded by an annular shaped donor electrode assembly 83, as
shown in FIG. 6. The electrode assembly positions in FIG. 6 can be
interchanged, with an annular shaped counter electrode assembly
surrounding a centrally positioned donor electrode assembly.
Alignment of the two electrode assemblies shown in FIG. 6 may be
circular, elliptical, rectangular, or any other consistent
geometric configuration.
The combined skin-contacting areas of the donor and counter
electrode assemblies 13 and 15 in FIG. 1 can vary from 1 cm.sup.2
to greater than 200 cm.sup.2. A typical device will have donor and
counter electrode assemblies with a combined skin-contacting area
in the range of 5-50 cm.sup.2.
Having thus generally described in detail our invention and certain
embodiments thereof, it will be readily apparent that various
modifications to the invention may be made by others skilled in the
art without departing from the scope of this invention and which is
limited only by the following claims.
* * * * *